Antifungal agents of sordarin derivatives

ABSTRACT

Sordarin derivatives prepared from C-11-hydroxysordarin are antifungal agents useful in the treatment and/or prevention of human and animal fungal infections, as well as in the control of phytopathogenic fungi in crops.

This application is the National Stage of International Application No.PCT/US02/22152, filed on Jul. 12, 2002, which claims the benefit under35 U.S.C. 119(e) of U.S. Provisional Application No. 60/306,358 filed onJul. 18, 2001.

FIELD OF INVENTION

The present invention relates to a class of novel compounds derived fromC-11-hydroxysordarin that are useful as an antifungal agent.

BACKGROUND OF THE INVENTION

Sordarin is an antifungal antibiotic isolated from the mould Sordariaaraneosa (see GB 1,162,027 and Helvetica Chimica Acta, 1971, 51:119-20).Other compounds having the sordarin skeleton have also been reported asantifungal agents. Japanese Kokai J62040292 discloses the compoundzofimarin isolated from Zofiela marina sp.; Japanese Kokai J06157582discloses the compound BE-31405 isolated from Penicillium sp.; andSCH57404 is reported in J. Antibiotics, 1995, 48:1171-1172.Semi-synthetic sordarin derivatives are reported in PCT ApplicationsWO96/14326 and WO96/14327.

Sordaricin, the aglycone, may be obtained from sordarin by acidhydrolysis (Hauser and Sigg, Helvetica Chimica Acta, 1971, 51:119-20).The total synthesis of sordaricin methyl ester is reported in Kato etal., J. Chem. Soc., Chem. Commun., 1993, 1002-1004, which also discloseso-methoxymethyl sordaricin methyl ester. The diacetate of4-deformyl-4-hydroxymethyl sordaricin is disclosed in Mander andRobinson, J. Org. Chem., 1991, 56(11):3395-3601. Neither sordaricin northe reported derivatives thereof has been shown to have biologicalactivity.

Balkovec et al. (U.S. Pat. Nos. 6,040,463 and 6,136,853) discloses acompound of sordarin derivative.

Nielsen-Kahn et al. (U.S. Pat. No. 5,972,996) and Tse, Bruno (U.S. Pat.No. 5,965,612) disclose a compound of 4-cyano-4-deformylsordarinderivatives.

Sturr et al. (U.S. Pat. No. 6,228,622) discloses a compound ofC11-hydroxysodarin and a process for producing it using Actinomyces spp,(Merck Culture Collection MA7235) by a biotransformation.

An objective of the present invention is to provide a novel class ofsordarin analogues derived from C-11-hydroxysordarin that are potentantifungal agents for general use and against pathogens associated withhuman and agricultural fungal infections.

SUMMARY OF THE INVENTION

The present invention relates to a novel compound of sordarin analoguesderived from C-11-hydroxysordarin. These novel compounds are potentantifungal agents with a broad spectrum of activity, which can be usedagainst pathogens associated with human and agricultural fungalinfections. The present invention also include a method for preparingsordarin analogues, a pharmaceutical and agricultural compositioncontaining the compounds, a method of treatment or prevention of afungal infection in humans and animal, and a method of controllingfungal infections in humans, animals and plant materials using suchcompounds.

The present invention is directed to a compound of formula I:

or a pharmaceutically or agriculturally acceptable salt thereof,wherein,

-   R is:    -   (a) hydrogen,    -   (b) C(O)OR¹,    -   (c) C(O)NR²R³,    -   (d) C(O)R⁴,    -   (e) CH(R²)OR⁵,    -   (f) C(R⁶)(R⁷)(R⁸),    -   (g)    -   (h)-   R¹ is:    -   (a) (C₁-C₁₄)alkyl,    -   (b) (C₂-C₁₄)alkenyl,    -   (c) (C₂-C₁₄)alkynyl,    -   (d) (C₃-C₂₀)cycloalkyl,    -   (e) aryl or    -   (f) aryl-(C₁-C₆)alkyl;-   R² and R³ are independently:    -   (a) H or    -   (b) R¹;-   R⁴ is:    -   (a) H,    -   (b) R¹ or    -   (c) (CH₂)_(m)NR²R³;-   R⁵ is:    -   (a) R¹ or    -   (b) (CH₂)_(x)O(CH₂)_(y)H;-   R⁶ is:    -   (a) H,    -   (b) (C₁-C₁₄)alkyl,    -   (c) aryl,    -   (d) aryl-(C₁-C₆)alkyl,    -   (e) (CH₂)_(y)CHR⁹(CH₂)_(z)H,    -   (f) (CH₂)_(y)C≡C(CH₂)_(z)H,    -   (g) (CH₂)_(y)C(R⁷)═CH(CH₂)_(z)H,    -   (h) (CH₂)_(y)C≡C(CH₂)_(m)R⁹ or    -   (i) (CH₂)_(y)C(R⁷)═CH(CH₂)_(m)R⁹;-   R⁷ and R⁸ are independently:    -   (a) H or    -   (b) (C₁-C₁₄)alkyl;-   R⁹ is:    -   (a) OH or    -   (b) NR²R³;-   R¹⁰ is:    -   (a) C(O)H or    -   (b) CN;-   R¹¹ is:    -   (a) H,    -   (b) —CH₂CH═CH₂,    -   (c)    -   (d)-   X¹ and X² are independently:    -   (a) H, wherein X¹ and X² are not H simultaneously,    -   (b) (C₁-C₆)alkyl,    -   (c) (C₁-C₆)alkoxy,    -   (d) (C₂-C₆)alkenyl optionally substituted with R¹,    -   (e) OH, wherein X¹ and X² are not OH simultaneously,    -   (f) OC[(C₁-C₆)alkyl]₃,    -   (g) OC(O)(C₁-C₆)alkyl,    -   (h) halo, wherein halo is F, Cl, Br or I,    -   (i) SC(O)(C₁-C₆)alkyl,    -   (j) S(C₁-C₆)alkyl,    -   (k) SH,    -   (l) N₃,    -   (m) N[(C₁-C₆)alkyl]₂,    -   (n) N[(C₁-C₆)alkyl]C(O)(C₁-C₆)alkyl or    -   (o)CN; and        wherein X¹ and X² together can be oxo or ═CH₂;-   n is: 0 or 1;-   m is: 1-6;-   p is: 0-5;-   x is: 2-6;-   y is: 0-6; and-   z is: 0-6.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of sordarin analoguesderived from C-11-hydroxysordarin, which is a potent antifungal agentwith a broad spectrum of activity to treat a diseases associated withhuman and agricultural fungal infections.

The present invention is directed to a compound of formula I:

or a pharmaceutically or agriculturally acceptable salt thereof,wherein,

-   R is:    -   (a) hydrogen,    -   (b) C(O)OR¹,    -   (c) C(O)NR²R³,    -   (d) C(O)R⁴,    -   (e) CH(R²)OR⁵,    -   (f) C(R⁶)(R⁷)(R⁸),    -   (g)    -   (h)-   R¹ is:    -   (a) (C₁-C₁₄)alkyl,    -   (b) (C₂-C₁₄)alkenyl,    -   (c) (C₂-C₁₄)alkynyl,    -   (d) (C₃-C₂₀)cycloalkyl,    -   (e) aryl or    -   (f) aryl-(C₁-C₆)alkyl;-   R² and R³ are independently:    -   (a) H or    -   (b) R¹;-   R⁴ is:    -   (a) H,    -   (b) R¹ or    -   (c) (CH₂)_(m)NR²R³;-   R⁵ is:    -   (a) R¹ or    -   (b) (CH₂)_(x)O(CH₂)_(y)H;-   R⁶ is:    -   (a) H,    -   (b) (C₁-C₁₄)alkyl,    -   (c) aryl,    -   (d) aryl-(C₁-C₆)alkyl,    -   (e) (CH₂)_(y)CHR⁹(CH₂)_(z)H,    -   (f) (CH₂)_(y)C␣C(CH₂)_(z)H,    -   (g) (CH₂)_(y)C(R⁷)═CH(CH₂)_(z)H,    -   (h) (CH₂)_(y)C≡C(CH₂)_(m)R⁹ or    -   (i) (CH₂)_(y)C(R⁷)═CH(CH₂)_(m)R⁹;-   R⁷ and R⁸ are independently:    -   (a) H or    -   (b) (C₁-C₁₄)alkyl;-   R⁹ is:    -   (a) OH or    -   (b) NR²R³;-   R¹⁰ is:    -   (a) C(O)H or    -   (b) CN;-   R¹¹ is:    -   (a) H,    -   (b) —CH₂CH═CH₂,    -   (c)    -   (d)-   X¹ and X² are independently:    -   (a) H, wherein X¹ and X² are not H simultaneously,    -   (b) (C₁-C₆)alkyl,    -   (c) (C₁-C₆)alkoxy,    -   (d) (C₂-C₆)alkenyl optionally substituted with R¹,    -   (e) OH, wherein X¹ and X² are not OH simultaneously,    -   (f) OC[(C₁-C₆)alkyl]₃,    -   (g) OC(O)(C₁-C₆)alkyl,    -   (h) halo, wherein halo is F, Cl, Br or I,    -   (i) SC(O)(C₁-C₆)alkyl,    -   (j) S(C₁-C₆)alkyl,    -   (k) SH,    -   (l) N₃,    -   (m) N[(C₁-C₆)alkyl]₂,    -   (n) N[(C₁-C₆)alkyl]C(O)(C₁-C₆)alkyl or    -   (o)CN; and        wherein X¹ and X² together can be oxo or ═CH₂;-   n is: 0 or 1;-   m is: 1-6;-   p is: 0-5;-   x is: 2-6;-   y is: 0-6; and-   z is: 0-6.

A preferred embodiment of the present invention provides the compound offormula I, wherein

-   R is: (a) hydrogen,    -   (b) C(O)OR¹,    -   (c) C(O)NR²R³,    -   (d) C(O)R⁴,    -   (e) CH(R²)OR⁵,    -   (f) C(R⁶)(R⁷)(R⁸),    -   (g)    -   (h)-   R¹⁰ is: C(O)H; and-   X¹ and X² are independently:    -   (a) H, wherein X¹ and X² are not H simultaneously,    -   (b) (C₁-C₆)alkyl,    -   (c) (C₁-C₆)alkoxy,    -   (d) (C₂-C₆)alkenyl optionally substituted with R¹,    -   (e) OH, wherein X¹ and X² are not OH simultaneously,    -   (f) OC[(C₁-C₆)alkyl]₃,    -   (g) OC(O)(C₁-C₆)alkyl,    -   (h) halo, wherein halo is F, Cl, Br or I,    -   (i) SC(O)(C₁-C₆)alkyl,    -   (j) S(C₁-C₆)alkyl,    -   (k) SH,    -   (l) N₃,    -   (m) N[(C₁-C₆)alkyl]₂,    -   (n) N[(C₁-C₆)alkyl]C(O)(C₁-C₆)alkyl or    -   (o)CN; and        wherein X¹ and X² together can be oxo or ═CH₂.

Another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is: (a) hydrogen,    -   (b) C(O)OR¹,    -   (c) C(O)NR²R³,    -   (d) C(O)R⁴,    -   (e) CH(R²)OR⁵,    -   (f) C(R⁶)(R⁷)(R⁸),    -   (g)    -   (h)-   R¹⁰ is: C(O)H;-   R¹ is: H; and-   X¹ and X² are independently H or halo, wherein either X¹ or X² is    halo.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is: C(O)OR¹;-   R¹⁰ is: C(O)H;-   R¹¹ is: H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is C(O)NR²R³;-   R¹⁰ is C(O)H;-   R¹¹ is H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is: C(O)R⁴;-   R¹⁰ is: C(O)H;-   R¹¹ is: H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is: C(R²)OR⁵;-   R¹⁰ is: C(O)H;-   R¹ is: H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is: C(R⁶)(R⁷)(R⁸);-   R¹⁰ is: C(O)H;-   R¹¹ is: H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is-   R¹⁰ is C(O)H;-   R¹¹ is H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is-   R¹⁰ is C(O)H;-   R¹¹ is H; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is-   R¹⁰ is C(O)H;-   R¹¹ is H; and-   X¹ and X² are independently H or Cl, wherein either X¹ or X² is Cl.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R is: CH(R⁶)(R⁷);-   R¹⁰ is: C(O)H;-   R¹¹ is: H;-   R⁶ is: (a) H,    -   (b) (C₁-C₁₄)alkyl,    -   (c) aryl,    -   (d) aryl-(C₁-C₆)alkyl,    -   (e) (CH₂)_(y)CH(OH)(CH₂)_(z)H or    -   (f) (CH₂)_(y)C(R⁷)═CH(CH₂)_(z)H;-   R⁷ is: H or (C₁-C₁₄)alkyl; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompound of formula I, wherein

-   R¹⁰ is: C(O)H;-   R¹¹ is: H;-   R is: (a) (C₁-C₇)alkyl,    -   (b) aryl-(C₁-C₆)alkyl,    -   (c) (CH₂)_(y)CH═CH(CH₂)_(z)H,    -   (d) [(C₁-C₆)alkyl]—CH₂CH═CHCH₂CH₃ or    -   (e) [(C₁-C₆)alkyl]—CH₂CH═CH(CH₂)₂CH₃; and-   X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.

Yet another preferred embodiment of the present invention provides thecompounds as shown in the table below:

(1S,3aR,4S,8aS)-6-(acetyloxy)-8a- [(acetyloxy)methyl]-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1S,3aR,4S,8aS)-6-(methoxy)-8a- [(methoxy)methyl]-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1S,3aR,4S,8aS)-6-(propoxy)-8a- [(propoxy)methyl]-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-6- (butoxymethyl)-4-formyl-6-hydroxy-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-4,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-chloro-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-azido-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-4-formyl-6-hydroxy-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-4-formyl-3-isopropyl-6-methoxy-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-fluoro-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-cyano-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (hydroxymethyl)-4-formyl-3-isopropyl-6-chloro-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-6-chloro-4- formyl-3-isopropyl-7-methyl-8a-{[(7-methyl-3- methylenehexahydro-2H- furo[2,3-c]pyran-5-yl)oxy]methyl}-4,4a,5,6,7,7a,8,8a-octahydro-1,4- methano-s-indacene-3a(1H)- carboxylicacid

Another aspect of the present invention provides a pharmaceuticalcomposition, which comprises a compound of formula I and apharmaceutically acceptable carrier.

Yet another aspect of the present invention provides a pharmaceuticalformulation comprising a combination of a compound of formula I and asecond therapeutic agent or its pharmaceutically acceptable salt. Thesecond therapeutic agent is a compound selected from the groupconsisting of an azole, polyene, purin uncleotide inhibitor,pneumocandin derivative, echinocandin derivative, the elongation factorinhibitor, and immunomodulating agent. A preferred second therapeuticagent is a compound selected from the group consisting of intraconazole,flucytosine, fluconazole, and amphotericin B.

Yet another aspect of the present invention provides an agrochemicalcomposition, which comprises a compound of formula I and anagriculturally acceptable carrier.

Yet another aspect of the present invention provides an agrochemicalcomposition, which comprises a compound of formula I and a second activeingredient selected from the group consisting of herbicides,insecticides, bactericides, nematocides, molluscicides, growthregulators, micronutrients, fertilizers, and fungicides.

Yet another aspect of the present invention provides a method for thetreatment or prevention of a fungal infection in a mammal (includinghumans), which comprises administering to said mammal therapeuticallyeffective amounts of a compound of formula I.

Yet another aspect of the present invention provides a method for thetreatment or prevention of fungal infection in a mammal, which comprisesadministering to said mammal therapeutically effective amounts of acompound of formula I and a second therapeutic agent selected from thegroup consisting of an azole, polyene, purin nucleotide inhibitor,pneumocandin derivative, echinocandin derivative, elongation factorinhibitor, and immunomodulating agent.

Yet another aspect of the present invention provides a method forcontrolling phytopathogenic fungi, which comprises administering to aplant in need of such control therapeutically effective amounts of acompound of formula I.

A further aspect of the present invention provides a method forcontrolling phytopathogenic fungi, which comprises administering to aplant in need of such control therapeutically effective amounts of acompound of formula I and a second active ingredient selected from thegroup consisting of herbicides, insecticides, bactericides, nematocides,molluscicides, growth regulators, micronutrients, fertilizers, andfungicides.

As used herein, unless otherwise specified, the following terms have theindicated meanings.

The term “alkyl”, alone or as part of a group (e.g. aryl-alkyl), means astraight or branched chain alkyl moiety, optionally substituted withcycloalkyl or cycloalkenyl, having the designated number of carbon atomssuch as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl,isopentyl, s-butyl, t-butyl, n-hexyl, n-octyl, decyl, undecyl,cyclopropylmethyl, cyclobutylmethyl, 2-cyclopentylethyl,cyclododecylmethyl, cyclohexylmethyl and the like.

The term “cycloalkyl” means a saturated carbocycle containing one ormore rings of from 3 to 12 carbon atoms, optionally substituted withC₁₋₃ alkyl. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, adamantyl,2-ethyl-1-bicyclo[4.4.0]decyl, and the like.

The term “aryl”, alone or as part of a group (e.g. aryl-alkyl), includesphenyl, biphenyl, terphenyl, naphthyl, anthracenyl or heteroaryl eachoptionally substituted by one to three groups independently selectedfrom halogen, hydroxyl, carboxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₄alkoxycarbonyl. The heteroaryl group may be a 5- or 6-memberedheteroaromatic ring containing one to three heteroatoms selected fromnitrogen, oxygen and/or sulfur. Examples of heteroaryl groups include,but are not limited to: pyridyl, quinolinyl, furyl, thienyl andpyrrolyl.

The term “alkenyl” means a straight or branched carbon chain having atleast one carbon-carbon double bond. Examples include vinyl, allyl,butenyl, isobutenyl, butadienyl, and the like.

The term “cycloalkenyl” means an unsaturated carbocycle containing oneor more rings of from 3 to 12 carbon atoms, optionally substituted withC₁₋₃ alkyl. Examples of cycloalkenyl groups are cyclobutenyl,cyclopentenyl, cyclohexenyl, methylcyclohexenyl, and the like.

The term “alkynyl” means a straight or branched carbon chain having atleast one carbon-carbon triple bond. Examples include acetylenyl,propargyl, butynyl, 1,3-pentadiynyl, and the like.

The term “controlling”, used in association with phytopathogenic fungi,includes prophylactic use (i.e. to protect against infection) andcurative use (i.e. to eradicate infection).

The term “plants” include live plants, foliage, flowers, seeds, fruits,and other materials derived from plants. The term also includes roots ofthe plant via application of the active ingredient to the soil.

The term “composition”, as in pharmaceutical or agriculturalcomposition, is intended to encompass a product comprising the activeingredient(s), and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation, aggregation or other interactions of any twoor more of the active ingredient(s) and/or the inert ingredient(s) orfrom dissociation of one or more of the active ingredient(s) and/or theinert ingredient(s), or from other types of reactions of one or more ofthe active ingredient(s) and/or the inert ingredient(s).

Suitable salts of a compound of formula I include inorganic base saltssuch as alkali metal salt (e.g. sodium and potassium salts), ammoniumsalts, and organic base salts. Suitable organic base salts include aminesalts such as tetraalkylammonium (e.g. tetrabutylammonium ortrimethylcetylammonium), trialkylamine (e.g. triethylamine),dialkylamine salts (e.g. dicyclohexylamine), optionally substitutedbenzylamine (e.g. phenylbenzylamine or parabromobenzylamine),ethanolamine, diethanolamine, N-methylglucosamine, N-methylpiperidine,pyridine and substituted pyridine (e.g. collidine, lutidine,4-dimethylaminopyridine), and tri(hydroxymethyl)methylamine salts, andamino acid salts (e.g. lysine or arginine salts).

A mammal as used in here includes a human and a warm blooded animal suchas a cat, a dog and the like.

The present invention of sordarin analogues of formula I are preparedfrom C11-hydroxysordarin as shown below, which is described in U.S. Pat.No. 6,228,622 B1.

C-11-hydroxysordarin

As disclosed in U.S. Pat. No. 6,228,622 B1, C-11-hydroxysordarin isprepared by a process of biotransformation of sordarin (II). The processinvolves a fermentation of the microorganism Actinomyces spp. MA7325,ATCC No. 202103 in the presence of the substrate compound, sordarin ofthe formula given below under appropriate conditions in an aqueousnutrient medium containing sources of assimilable carbon and nitrogen.

Sordarin (II)

A sample of the microorganism Actinomyces spp. has been deposited underthe Budapest Treaty in the culture collection of the American TypeCulture Collection, 10801 University Boulevard, Manassas, Va.,20110-2209, on Apr. 1, 1998 and assigned accession number ATCC 202103.

MA7235 can be generally described as follows. Observations of growth,and general cultural characteristics were made in accordance with themethods of Shirling and Gottleib (International J. System. Bacteriol.16:313-340). Chemical composition of the cells was determined using themethods of Lechevalier and Lechevalier (in Actinomycete Taxonomy, A.Dietz and D. W. Thayer, Ed. Society for Industrial Microbiology, 1980).Whole Cell Fatty Acids were derivatrized and analyzed as methyl esthers(Fames) by Gas Chromatography by the procedure of Miller and Bergerusing as MIDI Microbial Identification system (Microbial IdentificationSystems, Newark, Del.). Coloration of the culture was determined bycomparison with color standards in the Munsell color charts (MacbethDivision of Kollmorgen Instruments Corp. P.O. Box 230 Newburgh, N.Y.12551-0230).

The compounds of the present invention (the compounds of formula I) areprepared by the following reaction schemes and examples. The conditionsare representative and are not meant to be limiting.

Reaction Scheme 1 shows the hydrolysis of C-11-hydroxysordarin togenerate the aglycone. The aglycone can be prepared by treatingC-11-hydroxysordarin with hydrochloric acid in a polar solvent such asacetone. The carboxyl group is first protected with a suitableprotecting group, such as —CH₂C₆H₄(OCH₃) or —CH₂OC(O)C(CH₃)₃ and thenthe hydroxyl group at C-11 are protected with the same or an alternatesuitable protecting group. Selective protection at C-11, as its TBS(tert-butyldimethylsilyl) ether, allows the formation of derivatives atC-19 position as illustrated in the following Reaction Schemes 2-5.

Reaction Scheme 2 illustrates the synthesis of carbamate, ester andcarbonate derivatives of sordarin aglycone. The preparation ofcarbamates may be carried out by treatment of suitably protectedsordarin aglycone with an isocyanate (in the examples where R³ is H) ora carbamoyl halide or other activated carbamoylating agent in an inertsolvent. Removal of the protecting group produces a carbamate compoundof formula I.

Ester derivatives may be prepared in a similar fashion by treatment ofprotected sordarin aglycone with an activated carbonyl compound such asan acid chloride or mixed anhydride preferably in the presence of anacylation catalyst such as N,N-dimethylaminopyridine and a base such aspyridine. Removal of the protecting group yields an ester compound offormula I.

Carbonate derivatives may be prepared by the treatment of protectedsordarin aglycone with an activated carbonate such as a chloroformate orpyrocarbonate. An acylation catalyst such as N,N-dimethylaminopyridineand a base such as pyridine is preferably employed in the reactionmixture. Removal of the protecting group yields a carbonate compound offormula I.

Reaction Scheme 3 shows the synthesis of ether derivatives of sordarinaglycone. Treatment of the carboxylic acid-protected aglycone with anα-haloether under basic conditions or a vinyl ether under acidicconditions produce the substituted α-alkoxyether derivatives. Treatmentof protected sordarin aglycone with a primary or secondary halide orsulfonate and a suitable base such as sodium hydride under S_(N)2reaction conditions gives the corresponding primary or secondary etherderivatives, whereas treatment of the aglycone with a tertiary alcohol,halide or sulfonate and a Lewis acid under S_(N)1 conditions afford thecorresponding tertiary ether derivative. Removal of the protecting groupfrom the compound give a compound of formula I.

Reaction Scheme 4 shows the preparation of cyclic acetals from protectedsordarin aglycone. Treatment of the aglycone with a cyclic vinyl etherin the presence of an acid catalyst followed by removal of theprotecting group gives a compound of formula I.

Reaction Scheme 5 provides an additional method of derivation at C-19via the reaction with an activated sugar unit such as its imidate in thepresence of Lewis acid such as ZnCl₂ to generate a new sugar. ThisC-11-hydroxysordarin compound can be further reacted to give a compoundcontaining a halo substituent, such as Cl, Br, I or F at C-11 position.

Reaction Scheme 6 provides the transformation at C-11 position throughS_(N)2 reaction after removing the tert-butyldimethylsilyl (TBS) etherat C-11 to generate the free alcohol derivative of sordarin aglycone.The reaction involves the initial formation of a triflate from alcohol.The triflate is then displaced by various nucleophiles under S_(N)2reaction conditions to yield the derivatives. Removal of the protectinggroup gives the final sordarin C-11 derivatives of a compound of formulaI.

Reaction Scheme 7 shows the transformation at C-11 position throughS_(N)2 reaction after removing tert-butyldimethylsilyl ether at C-11 togenerate the free alcohol derivative of sordarin aglycone. The reactioninvolves the oxidation of the alcohol to the corresponding ketone.Subsequent reaction with a Grignard reagent, R¹CH₂MgX, followed bydehydration with Burgess' reagent[(methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt]affords the exocyclic double bond. The alkene formed could be reducedunder hydrogenation conditions to generate an alkyl derivative.Alternatively, the alkene could react under S_(N)1 reaction condition toafford another set of derivatives. Removal of the protecting groupaffords the final sordarin C-11 derivatives of a compound of formula I.

Reaction Scheme 8 provides another synthetic route to generate analogsat the C-11 position, which first modifies C-11 and then C-19 to producea compound of formula (I).

Reaction Scheme 9 shows the preparation of carboxy-protected4-cyano-4-deformylsordarin having hydroxy group at C-11. The sordarinnitrile analogues can be formed in the same way as in the formation ofsordarin aldehyde analogues, which are described in Reaction Schemes1-8. The alcohols and the carboxylic acid are first globally protectedas benzyl ethers or in other protected forms. The formyl group istransformed to the aldoxime, which is then dehydrated to the nitrile(cyano group) with a suitable agent such as Burgess's reagent,(methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt. Aftera universal deprotection, the nitrile analog is formed, which is thenundergoes transformation at C-11 or C-19 as shown in Reaction Schemes1-8.

Utility

The compounds of formula I are antifungal agents useful as human andanimal medicaments, as well as crop protectants.

Elongation factor 2 (EF2) is an essential protein catalyzing ribosomaltranslocation during protein synthesis in eukaryotic cells. It is highlyconserved in all eukaryotes, and has been found to be largelyinterchangeable in in-vitro protein synthesis systems reconstituted fromsuch divergent organisms as human, wheat germ and fungi. The sordarincompounds have been identified to be selective inhibitors of fungalprotein synthesis via a selective interaction with fungal EF2, which caneradicate invading organisms while sparing the host of any detrimentaleffects.

The compounds of formula I are very active fungicides useful incombating fungal infections in animals, including humans. For example,they may be used in the treatment of fungal infections caused byorganisms such as species of Candida (e.g. Candida glabrata, (Torulopsisglabrata), Candida lusitaniae, Candida parapsilosis, Candida krusei,Candida guilliermondi, Candida tropicalis, and Candidapseudotropicalis), Cryptococcus neoformans, Pneumocystis carinii,Aspergillus Sp (e.g. Aspergillus flavus, Aspergillus fumigatus andAspergillus nidulans), Coccidioides (e.g. Coccidioides immitis),Paracoccidioides (e.g. Paracoccidioides brasiliensis), Histoplasma (e.g.Histoplasma capsulatum), Blastomyces (e.g. Blastomyces dermatitidis) orSaccharomyces (e.g. Saccharomyces cerevisiae). They may also be used totreat other fungal infections caused by species of Trichophyton,Microsporum or Epidermophyton (e.g. Trichophyton mentographytes,Trichophyton rubrum, Microsporum canis or Epidermophyton floccosum), orin mucosal infections caused by Candida albicans.

The compounds of formula I may also be used to treat other infectionscaused by species of filamentous fungi such as Geotrichum (e.g.Geotrichum clavatum), Trichosporon (e.g. Trichosporon beigelii),Blastoschizomyces (e.g. Blastoschizomyces capitatus), Sporothrix (e.g.Sporothrix schenckii), Scedosporium (e.g. Scedosporium apiosperum),Cladosporium (e.g. Cladosporium carrionii) and Pityrosporum ovale.

The compounds of formula I may also be used to treat infections causedby protozoa such as Toxoplasma, Cryptosporidium, Leishmania,Tripanosoma, Giardia and Trichomonas.

The in-vitro evaluation of the anti-fungal activity of compounds of thepresent invention is performed on liquid or solid medium by theanti-fungal two-fold serial dilution technique of determining theminimum inhibitory concentration (MIC) of anti-fungal agent thatinhibited development of growth after 24 to 48 hours of incubation at35° C. In practice, a series of agar plates or broth microdilutionpanels containing two-fold dilutions of anti-fungal agent tested areinoculated with a standard culture of a clinically relevant pathogen,for example, Candida albicans. The agar plates or broth microdilutionpanels are then examined for the presence or absence of growth of thefungus and the appropriate MIC values were noted. Visualization ofendpoints is assisted by employment of the vital stain Alamar Blue.

The in-vitro assay evaluation of the antifungal activity of compounds offormula I to determine antifungal spectrum at the level of the EF2target can also be carried out as described below:

Assay procedure: S. cerevisiae ribosomes and post-ribosomal supernatantsare prepared from cultures of grown to mid-logarithmic phase in YPADmedium, which are washed twice with water and disrupted by shaking abouttwo hours at about 4° C. with 0.5 mm glass beads in buffer containing 50mM HEPES pH 7.5, 10% glycerol, 1 mM dithiothreitol and 1 mM EDTA. Aftercentrifugation of the lysate at 100,000×G, the ribosomal pellet iswashed three times by resuspension in 0.5M KCl, 20% sucrose and 10 mMMgCl2, and sedimentation at 100,000×G for about two hours. Ribosomes arethen resuspended in the breakage buffer as described above plus 2 mMMgCl₂ and their concentration is determined by absorbance at 260 Å. Thesupernatant from the original 100,000×G sedimentation after breakage isdesalted by passage through a Sephadex G10 column in the breakage bufferand protein is determined by Bradford assay. Both preparations arestored at about −70° C. without significant activity loss for up to ayear. Post-ribosomal supernatants and ribosomes from pathogenic Candidaare prepared the same way. In vitro incorporation is performed using0.05A₂₆₀ of ribosomes, from Saccharomyces cerevisiae, Candida spp orAspergillus nidulans and 3 μg of the corresponding S100 extract for each12.5 μL assay. Incorporation is performed for about 10 minutes at about22° C. in 12.5 μL volumes in microfuge tubes containing ribosomes andpost-ribosomal supernatant as listed above, 3H-phenylalanine (400dpm/pmol), 100 mM KCl, 33 mM HEPES pH 7.5, 14 mM MgCl₂, 400 nM ATP, 40nM GTP, 16 mM creatine phosphate, 3 mM dithiothreitol, 0.5 mg/mLpolyuridylic acid (Calbiochem) and 0.1 units creatine kinase (Sigma).After about 10 minutes incorporation, about 10 μL is spotted on aWhatman 3 mm filter disc numbered in pencil, and the disc is added to10% trichloracetic acid (5 ml/filter). When all discs are added, the TCAis heated to about 80° C. for about 10 minutes, and discs is washedtwice with ethanol and then dried for scintillation counting. Titrationis performed by sordarin derivatives diluted in 10% DMSO andincorporation plotted as a function of concentration. IC₅₀ values aredetermined from plots of incorporation in presence of increasing amountsof inhibitor versus incorporation in the presence of no inhibitor.

The in-vivo evaluation of compounds of formula I can be carried out at aseries of dose levels by administration (e.g. subcutaneously, orally,intraperitoneally or intravenously) to mice inoculated intravenouslywith a strain of Candida spp. The kidneys of the test animals may beremoved and quantitated for viable Candida spp. and the reduction ininfection may be determined relative to untreated control animals.

In view of their antifingal activity, compounds of formula I are usefulfor the treatment and/or prevention of a variety of fungal infections inhuman beings and animals. Such infections include superficial,cutaneous, subcutaneous and systemic mycotic infections such asrespiratory tract infections, gastrointestinal tract infections,cardiovascular infections, urinary tract infections, CNS infections,candidiasis and chronic mucocandidiasis (e.g. thrush and vaginalcandidiasis) and skin infections caused by fungi, cutaneous andmucocutaneous candidiasis, dermatophytoses including ringworm and tineainfections, athletes foot, paronychia, pityriasis versicolor,erythrasma, intertrigo, fungal diaper rash, candida vulvitis, candidabalanitis and otitis externa. They may also be used as prophylacticagents to prevent systemic and topical fungal infections. Use asprophylactic agents may, for example, be appropriate as part of aselective gut decontamination regimen in the prevention of infection inimmuno-compromised patients (e.g. AIDS patients, patients receivingcancer therapy or transplant patients). Prevention of fungal overgrowthduring antibiotic treatment may also be desirable in some diseasesyndromes or iatrogenic states.

The compounds of formula I also have use as broad spectrum cropantifingal agents and are effective on a broad spectrum ofphytopathogenic fungi, in particular those from the class consisting of:Deuteromycetes (e.g. Botrytis spp., Septoria spp., Pyricularia spp.,Stagnospora spp., Helminthosporium spp., Fusarium spp., Cercospora spp.,Rhynchosporium, spp. Pseudocercosporella, spp. and Alternaria spp.);Basidiomycetes (e.g. Puccinia spp., Rhizoctonia spp., and Hemileia);Ascomycetes (e.g. Venturia spp., Podospharera spp., Erysiphe spp.,Monilinia spp. and Uncinula spp.); and Oomycetes (e.g. Phytophthoraspp., Pemospora spp., Bremia spp., Pythium spp., and Plasmopara spp.).The foregoing list exemplifies the phytopathogenic fungi against whichthe named compounds demonstrate activity, and is not limiting in anymanner. These compounds have very advantageous curative and preventivefungicidal properties for protecting plants, and can be used to inhibitor to destroy the microorganisms occurring on plants or on parts ofplants (the fruit, blossom, leaves, stalks, tubers or roots) ofdifferent crops of useful plants, while at the same time parts of plantsthat grow later are also protected against such microorganisms. They canalso be used as dressings in the treatment of plant propagationmaterial, especially seed (fruit, tubers, grain) and plant cuttings (forexample rice), to provide protection against fungal infections andagainst phytopathogenic fungi occurring in the soil. Compounds offormula I of the invention are distinguished by the fact that they areespecially well tolerated by plants and are environmentally friendly.

Agricultural evaluation of a compound of formula I can be carried outusing the following tests.

1. Action Against Erysiphe graminis on Wheat.

a) After one-week cultivation, wheat plants are sprayed to run off witha spray mixture (200 ppm active ingredient/20% acetone/0.25% TritonX155). After 2 hours, the treated plants are infected with ascosporesshaken from inoculum plants. Fungal attack is evaluated after incubationfor 8 days at 22° C. at 50% relative humidity to determine theprotection given by the compound.

b) After one-week cultivation, wheat plants are infected with ascosporesshaken from inoculum plants. After 24 hours, the wheat plants aresprayed with a spray mixture (200 ppm active ingredient/20%acetone/0.25% Triton X155). Fungal attack is evaluated after incubationfor 8 days at 22° C. at 50% relative humidity to determine the degree ofcurative activity provided by the compound.

c) After one-week cultivation, wheat plants are infected with ascosporesshaken from inoculum plants. After 24 hours, the soil in which the wheatplants are growing is drenched with the drench mixture (200 ppm activeingredient/20% acetone/0.25% Triton X155). Fungal attack is evaluatedafter incubation for 8 days at 22° C. at 50% relative humidity todetermine the degree of curative activity provided by the compound.

2. Action Against Puccinia recondita on Wheat

a) After one-week cultivation, wheat plants sprayed to run off with aspray mixture (200 ppm active ingredient/20% acetone/0.25% Triton X155).After 2 hours, the treated plants are infected with a spore. Fungalattack is evaluated after incubation for one day at 95-100% relativehumidity at 20° C. followed by 7 days at 25° C. at 50% relative humidityto determine the protection given by the compound.

b) After one-week cultivation, wheat plants are infected with a sporesuspension. After 24 hours, the infected plants are sprayed to run offwith a spray mixture (200 ppm active ingredient/20% acetone/0.25% TritonX155. Fungal attack is evaluated after incubation for 1 day at 95-100%relative humidity at 20° C. followed by 7 days at 25° C. at 50% relativehumidity to determine the degree of curative activity provided by thecompound.

c). After one-week cultivation, wheat plants are infected with a sporesuspension. After 24 hours, the soil in which the wheat plants aregrowing was drenched with the drench mixture (200 ppm activeingredient/20% acetone/0.25% Triton X155). Fungal attack is evaluatedafter incubation for 1 day at 95-100% relative humidity at 20° C.followed by 7 days at 25° C. at 50% relative humidity to determine thedegree of curative activity provided by the compound.

Based on the spectrum of activity, the compounds of the presentinvention can be used to protect or cure plants of phytopathogenic fungiaffecting various useful crops. The following species of plants aresuitable for the use described in the scope of the invention of thestated compounds: cereal (e.g. wheat, rye, oat, barley, rice, sorghumand related crops); beet (sugar beet and fodder beet); pomes, dropes andsoft fruit (e.g. apples, pears, plums, peaches, almonds, cherries,strawberries, raspberries, and blackberries); leguminous plants (e.g.beans, peas, lentils and soybeans); oil plants (rape, mustard, poppy,olives, sunflowers, coconut, castor oil plants, cocoa beans andgroundnuts); curbitats (e.g. cucumber, squash, and melon); fiber plants(e.g. cotton, flax, hemp, and jute); citrus fruit (e.g. oranges, lemons,madarins and grapefruit); vegetables (e.g. lettuce, cabbage, spinach,carrot, asparagus, paprika, onions, tomatoes, and potatoes); lauraceae:(avocados, cinnamon and camphor); or plants such as maize, tobacco,nuts, coffee, sugar cane, tea, vines, hops, bananas and natural rubberplants, as well as ornamentals (flowers, shrubs, broad-leaved trees andevergreens, such as conifers). However, the aforementioned plant speciesdo not constitute a limiting list of plants with respect to spectrum bythe stated compounds.

The compounds of formula I are particularly useful for controlling thefollowing plant diseases:

Erysiphe graminis in cereals, Erysiphe cichoracearum and Sphaerothecafuliginea in cucurbits, Podosphaera leucotricha in apples, Uncinulanecator in vines, Puccinia species in cereals, Rhizoctonia solani incotton, Ustilago species in cereals and sugar cane, Venturia inaequalis(scab) in apples, Helminthosporium species in cereals, Septoria nodorumin wheat, Botrytis cinerea (gray mold) in strawberries and grapes,Cercospora arachidicola in groundnuts, Pseudocercosporellaherpotrichoides in wheat and barley, Pyricularia oryzae in rice,Phytophthora infestans in potatoes and tomatoes, Fusarium andVerticillium species in various plants, Plasmopara viticola in grapes,Alternaria species in fruit and vegetables. The compounds of formula Imay also be used for protecting materials (e.g. preservation of timberagainst Paecilomyces variotii).

Pharmaceutical Compositions.

While it is possible that, for use in therapy, compounds of the presentinvention may be administered as the raw chemical, it is preferable topresent the active ingredient in a pharmaceutical composition. Thepresent invention thus further provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, together with one or more pharmaceutically acceptablecarriers thereof and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The compositions of the present invention include those in a formespecially formulated for oral, buccal, parenteral, implant, rectal,topical, ophthalmic or genito-urinary administration or in a formsuitable for administration by inhalation or insufflation.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example, syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone;fillers, for example, lactose, sugar, microcrystalline cellulose,maize-starch, calcium phosphate or sorbitol; lubricants, for example,magnesium stearate, stearic acid, talc, polyethylene glycol or silica;disintegrants, for example, potato starch or sodium starch glycollate orcrosscarmellose sodium; or wetting agents such as sodium laurylsulphate. The tablets which include chewable, dispersible oreffervescent tablets may be coated according to methods well known inthe art. Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup, gelatin,hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gelor hydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan mono-oleate or acacia; non-aqueous vehicles (which may includeedible oils), for example, almond oil, fractionated coconut oil, oilyesters, propylene glycol or ethyl alcohol; and preservatives, forexample, methyl or propyl p-hydroxybenzoates or sorbic acid.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The composition according to the present invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

For administration by inhalation the compositions according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or froma nebulizer. In the case of a pressurized aerosol the dosage unit may bedetermined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation the compositionsaccording to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch or as a modified physical form ofthe drug substance alone. The powder composition may be presented inunit dosage form in, for example, capsules or cartridges of e.g.gelatin, or blister packs from which the powder may be administered withthe aid of an inhaler or insufflator.

The compositions may take the form of a suppository, e.g. containing aconventional suppository base, or a pessary, e.g. containing aconventional pessary base.

The compositions may also be formulated for topical administration inthe form of ointments, creams, gels, lotions, shampoos, powders(including spray powders), pessaries, tampons, sprays, dips, aerosols,drops (e.g. eye, ear or nose drops) or pour-ons. Ointments and creamsmay, for example, be formulated with an aqueous or oily base with theaddition of suitable thickening and/or gelling agents. Ointments foradministration to the eye may be manufactured in a sterile manner usingsterilized components. Pour-ons may, for example, be formulated forveterinary use in oils containing organic solvents, optionally withformulatory agents, e.g. stabilizing and solubilizing agents. Pessariesand tampons for vaginal insertion may be formulated using conventionaltechniques and, where appropriate, may contain an effervescent vehicle.Such compositions may also contain other active ingredients such ascorticosteroids, antibiotics or antiparasitics as appropriate.

Liquid preparations for intranasal delivery may take the form ofsolutions or suspensions and may contain conventional excipients such astonicity adjusting agents, for example, sodium chloride, dextrose ormannitol; preservatives, for example benzalkonium chloride, thiomersal,phenylethyl alcohol; and other formulating agents such as suspending,buffering, stabilizing, dispersing and or flavoring agents.

Transdermal administration may be affected by the design of a suitablesystem which promotes absorption of the active compound through the skinand would typically consist of a base formulation enclosed within anadhesive stick-on patch comprising backing films, membranes and releaseliners. Such systems may include absorption enhancers such as alcoholsor work by promoting ionotophoresis.

The composition according to the present invention may also beformulated as a depot preparation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, acompound of the invention may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

When the compositions comprise dosage units, each unit will preferablycontain 0.001 mg to 1000 mg, advantageously 0.01 mg to 400 mg, of activeingredient where a compound of the invention is to be administeredorally. The daily dosage as employed for adult human treatment willpreferably range from 0.001 mg to 5000 mg of active ingredient, mostpreferably from 0.01 mg to 2000 mg which may be administered in 1 to 4daily doses, for example, depending on the route of administration andon the condition of the patient and the disease to be treated.

The compound may be administered by intravenous infusion using, forexample, up to 50 mg/kg/day of the active ingredient. The duration oftreatment will be dictated by the rate of response rather than byarbitrary number of days.

The compounds of the present invention may also be used in combinationwith other therapeutic agents, and the invention thus provides, in afurther aspect, a combination comprising a compound of the inventiontogether with another therapeutically active agent.

Thus, for example the compounds of the present invention may be used incombination with one or more other antifungal agents, such as polyenes(e.g., amphotericin B, nystatin, and liposomal and lipid forms thereof);azole (e.g., fluconazole, intraconazole, detoconazole, miconazole,clotrimazole, voriconazole, ZD-08070, UK-109496, SCH 56592); purin orpyrimidine nucleotide inhibitors (e.g, 5-fluorocytosine, flucytosine);polyoxin (e.g, nikkomycin Z); a pneumocandin or echinocandin derivative(e.g., cilofungin, anidulafingin (V-echinocandin),1-[(4R,5S)-5-[(2-aminoethyl)oxy]-N²-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]pneumocandinB₀ and caspofingin (CANCIDAS™)); the elongation factor inhibitor(sordarin derivatives); or other cell wall active compound such as oneor more immunomodulating agents (e.g., an interferon e.g. (IFN-),interleukine e.g. (IL-1, IL-2, IL-3 and IL-8) and colony stimulatingfactors, [(G)-CSF, (M)-CSF and (GM)-CSF] and defensines).

Particularly preferred compounds for use with the compounds of thepresent invention include intraconazole, flucytosine, fluconazole oramphotericin B.

When the compounds of the present invention are administered incombination with another antifungal agent the compounds of the inventionand the other fungal agent can be administered at the recommendedmaximum clinical dosage or at lower doses.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier thereof comprise a further aspect ofthe invention. The individual components of such combinations may beadministered either sequentially or simultaneously in separate orcombined pharmaceutical formulations

When a compound of the invention is used in combination with a secondtherapeutic agent against the same condition the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

Agrochemical Compositions

The compounds of formula I can be used in either an unmodified form orpreferably together with adjuvants conventionally employed in the art ofagrochemical formulation and are for this purpose forms known mainly as:emulsifiable concentrates, coatable pastes, directly sprayable ordilutable solutions, dilute solution, suspensions (includinghigh-percentage aqueous, oily or other suspensions), dispersions, oildispersions, broadcasting agents, wettable powders, soluble powders,dusts, granules, and encapsulations. The formulations are prepared inknown manner, e.g. by homogeneously mixing and/or grinding the activeingredients with extenders, e.g. solvents, solid carriers and, whereappropriate, surface-active compounds (surfactants). Powders, dusts andbroadcasting agents may be prepared by mixing or grinding the activeingredients with a solid carrier. Granules, e.g., coated, impregnated orhomogeneous granules, may be prepared by bonding the active ingredientsto solid carriers.

Suitable solvents are: aromatic hydrocarbons, preferably the fractionscontaining 8 to 12 carbon atoms, such as xylene mixtures or substitutednaphthalenes, chlorinated aromatics such as chlorobenzenes, phthalates,such as dibutyl or dioctyl phthalate, aliphatic hydrocarbons, such ascyclohexane or paraffins, alcohols and glycols and their ethers andesters, such as ethanol, ethylene glycol, ethylene glycol monomethyl ormonoethyl ether, ketones such as cyclohexanone, amines such asethanolamine, strongly polar solvents, such as N-methyl-2-pyrrolidone,dimethyl sulfoxide or dimethylformamide, and vegetable oils orepoxidized vegetable oils, such as epoxidized coconut oil or soybeanoil; and water.

Examples of surfactants are: alkali metal, alkaline earth metal andammonium salts of aromatic sulfonic acids, e.g., ligninsulfonic acid,phenolsulfonic acid, naphthalenesulfonic acid anddibutylnaphthalenesulfonic acid, and of fatty acids, alkyl and alkylarylsulfonates, and alkyl, lauryl ether and fatty alcohol sulfates, andsalts of sulfated hexadecanols, heptadecanols, and octadecanols, saltsof fatty alcohol glycol ethers, condensation products of sulfonatednaphthalene and naphthalene derivatives with formaldehyde, condensationproducts of naphthalene or naphthalenesulfonic acids with phenol andformaldehyde, polyoxyethylene octylphenol ethers, ethoxylatedisooctylphenol, ethoxylated octylphenol and ethoxylated nonylphenol,alkylphenol polyglycol ethers, tributylphenyl polyglycol ethers,alkylaryl polyether alcohols, isotridecyl alcohol, fatty alcoholethylene oxide condensates, ethoxylated castor oil, polyoxyethylenealkyl ethers, ethoxylated polyoxypropylene, lauryl alcohol polyglycolether acetal, sorbitol esters, lignin-sulfite waste liquors and methylcellulose.

Examples of solid carriers are mineral earths such as silicic acids,silica gels, silicates, talc, kaolin, attapulgus clay, limestone, lime,chalk, bole, loess, clay, dolomite, diatomaceous earth, aluminas calciumsulfate, magnesium sulfate, magnesium oxide, ground plastics,fertilizers such as ammonium sulfate, ammonium phosphate, ammoniumnitrate, and ureas, and vegetable products such as grain meals, barkmeal, wood meal, and nutshell meal, cellulosic powders, etc.

The compounds of formula I may be mixed and applied together with otheractive ingredients, for example herbicides, insecticides, bactericides,nematocides, molluscicides, growth regulators, micronutrients, andfertilizers. The other ingredients may also be one or more fungicidesbelonging to but not restricted to the following classes of fungicides:carboxamides, benzimidazoles, triazoles, hydroxypyridines,dicarboxamides, phenylamides, thiadiazoles. carbamates, cyano-oximes,cinnamic acid derivatives, morpholines, imidazoles, B-methoxy acrylatesand pyridines/pyrimidines. Furthermore, these additional activeingredients may be used as mixtures of several of the preparations, ifdesired together with other application promoting adjuvants usually usedin the art of formulation. Suitable carriers and adjuvants can be solidor liquid and correspond to the substances typically used in formulationtechnology (e.g. natural or regenerated mineral substances, solvents,disperants, and wetting agents).

The following list of fungicides with which the compounds of formula Imay be combined is intended to illustrate possible combinations but notto impose any restrictions. Examples of fungicides which may be combinedwith the compounds of formula I are: sulfur, dithiocarbamates and theirderivatives, such as ferric dimethyldithiocarbamate, zincdimethyldithiocarbamate, zinc ethylenebisdithiocarbamate, manganeseethylenebisdithiocarbamate, manganese zincethylenediaminebisdithiocarbamate, tetramethylthiuram disulfides,ammonia complex of zinc N,N′-ethylenebisdithiocarbamate, ammonia complexof zinc N,N′-propylenebisdithiocarbamate, zincN,N′-propylenebisdithiocarbamate and N,N′-polypropylenebis(thiocarbamyl) disulfide; nitro derivative, such asdinitro(1-methylheptyl)-phenyl crotonate, 2-sec-butyl-4,6-dinitrophenyl3,3-dimethylacrylate, 2-sec-butyl-4,6-dinitrophenyl isopropylcarbonateand diisopropyl 5-nitroisophthalate; heterocyclic substances, such as2-heptadecylimidazol-2-yl acetate,2,4-dichloro-6-(o-chloroanilino)-s-triazine, O,O-diethylphthalimidophosphonothioate,5-amino-1-[bis-(dimethylamino)-phosphinyl]-3-phenyl-1,2,4-triazole,2,3-dicyano-1,4-dithioanthraquinone,2-thio-1,3-dithio[4,5-b]quinoxaline, methyl1-(butylcarbamyl)-2-benzimidazolecarbamate,2-methoxycarbonylaminobenzimidazole, 2-(fur-2-yl)-benzimidazole,2-(thiazol-4-yl)benzimidazole,N-(1,1,2,2-tetrachloroethylthio)-tetrahydrophthalimide,N-trichloromethylthiotetrahydrophthalimide,N-trichloromethylthiophthalimide,N-dichlorofluoromethylthio-N′,N′-dimethyl-N-phenylsulfuric acid diamide,5-ethoxy-3-trichloromethyl-1,2,3-thiadiazole,2-thiocyanatomethylthiobenzothiazole, 1,4-dichloro-2,5-dimethoxybenzene,4-(2-chlorophenylhydrazono)-3-methyl-5-isoxazolone, 2-thiopyridine1-oxide, 8-hydroxyquinoline and its copper salt,2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiyne,2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiyne 4,4-dioxide,2-methyl-5,6-dihydro-4H-pyran-3-carboxanilide,2-methylfuran-3-carboxanilide, 2,5-dimethylfuran-3-carboxanilide,2,4,5-trimethylfuran-3-carboxanilide,2,5-dimethyl-N-cyclohexylfuran-3-carboxamide,N-cyclohexyl-N-methoxy-2,5-diethylfuran-3-carboxamide,2-methylbenzanilide, 2-iodobenzanilide,N-formyl-N-morpholine-2,2,2-trichloroethylacetal,piperazine-1,4-diylbis-(1-(2,2,2-trichloroethyl)-formamide),1-(3,4-dichloroanilino)-1-formylamino-2,2,2-trichloroethane,2,6-dimethyl-N-tridecylmorpholine and its salts,2,6-dimethyl-N-cyclododecylmorpholine and its salts,N[3-(para-tert.-butylphenyl)-2-methylpropyl]-cis-2,6-dimethylmorpholine,N-[3-(para-tert.-butylphenyl)-2-methylpropyl]-piperidine,1-2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolan-2-yl-ethyl]-1H-1,2,4-triazole,1-[2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolan-2-yl-ethyl]-1H-1,2,4-triazole,N-(n-propyl)-N-(2,4,6-trichlorophenoxyethyl)-N]-imidazolylurea,1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-one,1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol,alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol,5-butyl-(2-dimethylamino-4-hydroxy-6-methylpyrimidine,bis-(p-chlorophenyl)-3-pyridinemethanol,1,2-bis-(3-ethoxycarbonyl-2-thioureido)-benzene,1,2-bis-(3-methoxycarbonyl-2-thioureido)-benzene, and variousfungicides, such as dodecylguanidine acetate,3-[3-(3,5-dimethyl-2-oxycyclohexyl)-2-hydroxyethyl]-glutaramide,hexachlorobenzene, DL-methyl-N-(2,6-dimethylphehyl)-N-fur-2-yl alanate,methyl DL-N-(2,6-dimethylphenyl)-N-(2]-methoxyacetyl)-alanate,N-(2,6-dimethylphenyl)-N-chloroacetyl-DL-2-aminobutyrolactone, methylDL-N-(2,6-dimethylphenyl)-N-(phenylacetyl)-alanate,5-methyl-5-vinyl-3-(3,5-dichlorophenyl)-2,4-dioxo-1,3-oxazolidine,3-[3,5-dichlorophenyl]-5-methyl-5-methoxymethyl-1,3-oxazolidine-2,4-dione,3-(3,5-dichlorophenyl)-1-isopropylcarbamylhydantoin,N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximide,2-cyano-[N-(ethylaminocarbonyl)-2-methoximino]-acetamide, 1-[2-(2,4dichlorophenyl)-pentyl]-1H-1,2,4-triazole,2,4-difluoro-a-(1H-1,2,4-triazol-1-ylmethyl)-benzhydryl alcohol,N-(3-chloro-2,6-dinitro-4trifluoromethylphenyl)-5-trifluoromethyl-3-chloro-2-aminopyridine, and1-((bis-(4-fluorophenyl)-methylsilyl)-methyl)-1H-1,2,4-triazole.

As with the nature of compositions, the method of application such asspraying, atomizing, dusting, scattering, coating, dressing, and pouringare chosen in accordance with the intended objectives of the applicationand the prevailing circumstances. One method of applying the activeingredient or agrochemical composition containing at least one of thestated compounds is application to the plants (i.e. foliar application).However, the active ingredient can also penetrate the plant through theroots via the soil (i.e. soil application). This may be in the form ofeither a liquid application to the soil (drench) or a granularapplication.

The active ingredient can also be applied to plant propagation materialsuch as seeds (fruits, tubers or grains) or plant cuttings, in eitherliquid form (coating) or in solid form (dressing). Seeds, for example,can be dressed before sowing. The compounds of the invention can also beapplied to grains either by impregnating the grains with a liquidformulation of by coating them with a solid formulation. The compositioncan also be applied to the locus of planting when planting thepropagation material, for example to the seed furrow during sowing.

Advantageous rates of application are normally from about 10 g to about50 kg of active ingredient (a.i.) per hectare, preferably about 100 g toabout 2 kg a.i./ha, most preferably about 100 g to about 600 g a.i./ha.The active ingredients of the stated compounds are typically used in theform of compositions and can be applied to the plant, or to parts of theplant either simultaneously or in succession with further activeingredients. These further active ingredients can be fertilizers,additional micronutrients, or other plant growth affecting compounds.They can, however, also be selective herbicides, insecticides,bactericides, nematocides, insecticides, and molluscicides, as well asother fungicides.

The following examples are provided to more fully illustrate thepreparation of the present invention, and as such not to be consideredas limiting the invention in any manner set forth in the claims appendedhereto.

EXAMPLE 1 4-methoxybenzyl(1R,3aR,4S,8aS)-4-formyl-6-hydroxy-8a-(hydroxmethyl)-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylate(4)

PMB is paramethoxybenzyl.

To a solution of 1 (95.1 mg, 0.19 mmol) in acetone (5 mL) was added 0.5mL of concentrated HCl. The mixture was stirred at room temperature forone day. After aqueous work-up (EtOAc), the mixture was concentrated invacuo and was dissolved in DMF (4 mL). About 0.13 mL of p-methoxybenzylchloride (MPMCl) (0.96 mmol) and NaHCO₃ (157.3 mg, 1.87 mmol) wereadded. The mixture was stirred at room temperature overnight. Afteraqueous work-up (ether) and purification by a Preparative Thin LayerChromatography (PTLC), about 58.7 mg of 4 was obtained.

EXAMPLE 2(1S,3aR,4S,8aS)-6-(acetyloxy)-8a-[(acetyloxy)methyl]-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (6)

To a solution of 4 (5.0 mg, 0.01 mmol) in pyridine (2 mL) was added 0.5mL of Ac₂O. The mixture was stirred at room temperature overnight. Afterconcentration in vacuo and purification by a PTLC, about 5.2 mg of 5 wasobtained. To a solution of 5 (5.2 mg) in CH₃OH (1.5 mL) was addedPearlman's catalys (Pd(OH)₂/C, 15 mg). The mixture was stirred under H₂(balloon pressure) for about 15 minutes. After filtration andconcentration in vacuo, about 3.9 mg of 6 was obtained.

¹H NMR (CDCl₈): δ0.92 ppm (3H, d, J=6.9), 0.99 (3H, d, J=6.2), 1.06 (3H,d, J=6.2), 1.16 (1H, m), 1.36 (1H, m), 1.80 (1H, m), 1.86 (1H, m), 2.03(3H, s), 2.05 (3H, s), 2.00-2.10 (4H, m), 2.39 (1H, m), 2.55 (1H, m),2.79 (1H, m), 4.25 (1H, d, J=10.7), 4.31 (1H, d, J=10.7), 4.75 (1H, m),6.15 (1H, br s), 9.60 (1H, s).

EXAMPLE 3(1S,3aR,4S,8aS)-6-(methoxy)-8a-[(methoxy)methyl]-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (8)

To a solution of 4 (5.0 mg, 0.01 mmol) in DMF (2 mL) was added CH₃I(0.02 mL, 0.3 mmol) and NaH (10 mg of a 60% oil dispersion, 0.25 mmol).The mixture was stirred at room temperature overnight. After aqueouswork-up (ether) and purification by a PTLC, about 4.7 mg of 7 wasobtained, which was dissolved in 1.5 mL of CH₃OH. Pearlman's catalyst(15 mg) was added and the mixture was stirred under H₂ (balloonpressure) for about 15 minutes. After filtration and concentration invacuo, about 4.7 mg of 8 was obtained.

¹H NMR (CDCl₃): δ0.89 ppm (3H, d, J=7.6), 1.00 (3H, d, J=6.7), 1.04 (3H,d, J=6.6), 1.30 (2H, m), 1.60 (1H, m), 2.00-2.18 (5H, m), 2.30-2.50 (3H,m), 3.29 (3H, s), 3.42(3H, s), 3.45 (1H, m), 3.56 (1H, d, J=9.1), 3.97(1H, d, J=9.1), 6.10 (1H, s), 9.79 (1H, s).

EXAMPLE 4(1S,3aR,4S,8aS)-6-(propoxy)-8a-[(propoxy)methyl]-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (10)

To a solution of 4 (5.5 mg, 0.012 mmol) in DMF (2 mL) was added allylbromide (0.02 mL, 0.23 mmol) and NaH (5 mg of a 60% oil dispersion, 0.13mmol). The mixture was stirred at room temperature overnight. Afteraqueous work-up (ether) and a PTLC, about 5.7 mg of 9 was obtained andwas dissolved in CH₃OH (1.5 mL). Pearlman's catalyst (15 mg) was added.The mixture was stirred under H₂ (balloon pressure) for about 15minutes. After filtration and concentration in vacuo, about 5.5 mg of 10was obtained.

¹H NMR (CDCl₈): δ0.92 ppm (3H, t, J=6.7), 0.94 (3H, d, J=7.0), 0.96 (3H,t, J=6.9), 0.98 (3H, d, J=6.8), 1.02 (3H, d, J=6.7), 1.28 (1H, d,J=12.6), 1.56-1.70 (6H, m), 2.00-2.20 (5H, m), 2.34-2.50 (3H, m), 3.27(1H, d, J=9.2), 3.30 (2H, m), 3.46 (2H, m), 3.52 (1H, m), 4.00 (1H, d,J=9.2), 6.09 (1H, d, J=3.2), 9.81 (1H, s).

EXAMPLE 5 4-methoxybenzyl(1R,3aR,4S,8aS)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-formyl-8a-(hydroxymethyl)-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylate(11)

To a solution of 4 (100 mg, 0.21 mmol) in CH₂Cl₂ (10 mL) was added Net₃(0.045 mL, 0.32 mmol), tert-butyldimethylsilyl chloride (TBSCl) (35.4mg, 0.23 mmol) and 4-dimethylaminopyridine (DMAP) (2 mg, 0.016 mmol).The mixture was stirred at room temperature overnight. Afterpurification by chromatography about 80.8 mg of 11 was obtained andabout 15 mg of 4 was recovered.

¹H NMR (CDCl₃): δ0.01 ppm (3H, s), 0.02 (3H, s), 0.52 (3H, d, J=6.7),0.85 (3H, d, J=6.6), 0.88 (9H, s), 0.96 (1H, m), 1.04 (3H, d, J=6.6),1.19 (1H, d, J=12.9), 1.44 (1H, m), 1.62 (1H, dd, J=6.4, 14.6), 1.77(1H, m), 1.82 (1H, dd, J=13, 14), 2.09 (2H, m), 2.30 (2H, m), 2.56 (1H,t, J=3.6), 2.78 (1H, br d, J=7.8), 3.46 (1H, m), 3.62 (1H, t, J=5.8),3.83 (3H, s), 3.90 (1H, d, J=11.7), 5.05 (1H, d, J=11.7), 5.30 (1H, d,J=11.7), 6.10 (1H, d, J=2.1), 6.89 (2H, d, J=8.5), 7.35 (2H, d, J=8.5),9.51 (1H, s).

EXAMPLE 6 4-methoxybenzyl(1R,3aR,4S,8aS)-8a-(butoxymethyl)-4-formyl-6-hydoxy-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylate(13)

To a solution of 11 (9.9 mg, 0.017 mmol) in DMF (10 mL) was added1-iodobutane (0.2 mL, 1.75 mmol) and NaH (100 mg of a 60% oildispersion, 2.5 mmol). The mixture was stirred at room temperatureovernight. After aqueous work-up (ether) and a PTLC purification, about9.9 mg of 12 was obtained and was dissolved in 10 mL of THF.Tetrabutylammonium fluoride (TBAF) (1.5 mL of a 1M solution in THF, 1.5mmol) was added. The mixture was stirred at room temperature for abouttwo hours. After concentration in vacuo and purification by a PTLC,about 7.2 mg of 13 was obtained.

¹H NMR (CDCl₃): δ0.55 ppm (3H, d, J=7.6 Hz), 0.85 (3H, d, J=6.6), 0.92(3H, t, J=7.4), 1.05 (3H, d, J=6.8), 1.23 (1H, d, J=12.6), 1.30-1.40(3H, m), 1.42-1.50 (3H, m), 1.60 (2H, m), 1.78 (1H, m), 1.92 (1H, dd,J=6.2, 14.2), 2.00 (2H, m), 2.28 (1H, m), 2.45 (1H, m), 2.50 (1H, m),2.81 (1H, m), 3.30 (1H, m), 3.37 (1H, d, J=8.9), 3.60 (1H, d, J=8.9),3.78 (1H, t, J=5.8), 3.80 (3H, s), 5.07 (1H, d, J=11.5), 5.18 (1H, d,J=11.5), 6.10 (1H, d, J=2.3), 6.89 (2H, d, J=8.7), 7.33 (2H, d, J=8.7),9.52 (1H, s).

EXAMPLE 7(1R,3aR,4S,8aS)-6-(butoxymethyl)-4-formyl-6-hydroxy-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (14)

To a solution of 13 (2 mg, 0.0038 mmol) in CH₃OH (2 mL) was addedPearlman's catalyst (10 mg). The mixture was stirred under H₂ (balloonpressure) for about 15 minutes. After filtration and concentration invacuo, about 1.5 mg of 14 was obtained.

¹H NMR (CDCl₁): δ0.89 ppm (3H, d, J=7.6 Hz), 0.90 (3H, t, J=7.4), 1.00(3H, d, J=6.6), 1.04 (3H, d, J=6.8), 1.30-1.40 (2H, m), 1.50-1.80 (4H,m), 1.95 (1H, m), 2.05 (1H, m), 2.10 (1H, m), 2.18 (1H, m), 2.25 (1H,m), 2.38 (1H, m), 2.42 (1H, m), 2.54 (2H, m), 3.28 (1H, d, J=9.3), 3.52(2H, m), 4.00 (1H, m), 4.01 (1H, d, J=9.3), 6.10 (1H, d, J=2.0), 9.80(1H, s).

EXAMPLE 8(1R,3aR,4S,8aS)-8a-(butoxymethyl)-6-chloro-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (16)

To a solution of 13 (8 mg, 0.015 mmol) in CH₂Cl₂ (2 mL) was added2,6-di-tert-butylpyridine (0.007 mL, 0.031 mmol) and Tf₂O (0.004 mL,0.024 mmol) at about 0° C. The mixture was stirred at about 0° C. forabout 30 minutes. Tetrabutylammonium chloride (70 mg, 0.31 mmol) wasadded. The mixture was stirred at room temperature overnight. Afteraqueous work-up (ether) and purification by a PTLC, about 6.6 mg of 15was obtained. To a solution of 15 (4.0 mg, 0.0074 mmol) in CH₃OH (2 mL)was added Pearlman's catalyst (10 mg). The mixture was stirred under H₂(balloon pressure) for about 15 minutes. After filtration andconcentration in vacuo, about 3.0 mg of 16 was obtained.

¹H NMR (CDCl): δ0.94 ppm (3H, t, J=7.3 Hz), 1.00 (3H, d, J=6.8), 1.01(3H, d, J=7.0), 1.07 (3H, d, J=6.6), 1.26 (1H, d, J=12.8), 1.38 (2H, m),1.58-1.70 (3H, m), 1.90 (2H, m), 1.98 (1H, m), 2.16 (1H, t, J=12.8),2.25 (1H, m), 2.40 (2H, m), 2.43 (1H, m), 2.50 (1H, m), 3.28 (1H, d,J=9.2), 3.50 (2H, m), 4.00 (1H, d, J=9.2), 4.49 (1H, m), 6.11 (1H, d,J=1.1), 9.75 (1H, s).

EXAMPLE 9(1R,3aR,4S,8aS)-8a-(butoxymethyl)-6-azido-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (18)

To a solution of 13 (8 mg, 0.015 mmol) in CH₂Cl₂ (2 mL) was added2,6-di-tert-butylpyridine (0.007 mL, 0.031 mmol) and Tf₂O (0.004 mL,0.024 mmol) at about 0° C. The mixture was stirred at about 0° C. forabout 30 minutes. To the mixtures was added tetrabutylammonium azide(1.5 mL of a 0.1M solution in toluene, 0.15 mmol). The mixture wasstirred at room temperature for one day. After concentration in vacuoand purification by a PTLC, about 7.1 mg of 17 was obtained. Theazido-compound 17 (2.5 mg, 0.0046 mmol) was dissolved in 2 mL of formicacid. The mixture was stirred at room temperature for about 30 minutes.After concentration in vacuo and purification by a PTLC, about 1.7 mg of18 was obtained.

¹H NMR (CDCl₃): δ0.91 ppm (3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.1), 1.00(3H, d, J=6.9), 1.07 (3H, d, J=6.9), 1.25 (2H, m), 1.38 (2H, m), 1.60(3H, m), 1.92 (1H, m), 1.95 (1H, m), 2.08 (1H, m), 2.15 (1H, m),2.32-2.45 (4H, m), 3.27 (1H, d, J=9.2), 3.50 (2H, m), 4.01 (1H, d,J=9.2), 4.14 (1H, m), 6.11 (1H, d, J=2.1), 9.76 (1H, s).

EXAMPLE 10(1R,3aR,4S,8aS)-8a-(butoxmethyl)-4-formyl-6-hydroxy-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (20)

To a solution of 13 (15 mg, 0.029 mmol) in CH₂Cl₂ (3 mL) was added2,6-di-tert-butylpyridine (0.013 mL, 0.058 mmol) and Tf₂O (0.007 mL,0.042 mmol) at about 0° C. The mixture was stirred at about 0° C. forabout 30 minutes. To the mixture was added ethylene glycol dimethylether (DME) (3 mL) and triton B (150 mg of a 40% solution in water, 0.36mmol). The mixture was stirred at room temperature for about one day.After aqueous work-up (CH₂Cl₂) and purification by a PTLC, about 10 mgof 19 was obtained. To a solution of 19 (2.0 mg, 0.0038 mmol) in CH₃OH(2 mL) was added Pearlman's catalyst (10 mg). The mixture was stirredunder H₂ (balloon pressure) for about 15 minutes. After filtration andconcentration in vacuo, about 1.5 mg of 20 was obtained.

¹H NMR (CDCl₃): δ0.90 ppm (3H, d, J=7.0 Hz), 0.92 (3H, t, J=6.8), 0.98(3H, d, J=6.7), 1.02 (3H, d, J=6.7), 1.30-1.40 (2H, m), 1.45-1.80 (4H,m), 1.80-2.00 (3H, m), 2.16 (1H, t, J=13.1), 2.30-2.42 (5H, m), 3.27(1H, d, J=8.9), 3.48-3.60 (2H, m), 4.01 (1H, d, J=8.9), 4.42 (1H, t,J=1.1), 6.09 (1H), d, J=2.5), 9.81 (1H, s).

EXAMPLE 11(1R,3aR,4S,8aS)-8a-(butoxymethyl)-4-formyl-3-isopropyl-6-methoxy-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (22)

To a solution of 19 (2 mg, 0.0038 mmol) in DMF (2 mL) was added CH₃I(0.01 mL, 0.16 mmol) and NaH (5 mg of a 60% oil dispersion, 0.13 mmol).The mixture was stirred at room temperature overnight. After aqueouswork-up (ether) and purification by a PTLC, about 1.9 mg of 21 wasobtained. To a solution of 21 (1.9 mg, 0.0035 mmol) in CH₃OH (2 mL) wasadded Pearlman's catalyst (10 mg). The mixture was stirred under H₂(balloon pressure) for about 15 minutes. After filtration andconcentration in vacuo, about 1.4 mg of 22 was obtained.

¹H NMR (CDCl): δ0.86 ppm (3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3), 0.99(3H, d, J=6.9), 1.06 (3H, d, J=6.6), 1.28 (2H, m), 1.38 (2H, m), 1.42(1H, m), 1.60 (2H, m), 1.90 (3H, m), 2.17 (1H, t, J=13.2), 2.38 (2H, m),2.41 (2H, m), 3.26 (1H, d, J=9.2), 3.30 (3H, s), 3.45-3.57 (2H, m), 3.86(1H, m), 4.00 (1H, d, J=9.2), 6.07 (1H, d, J=2.8), 9.84 (1H, s).

EXAMPLE 12(1R,3aR,4S,8aS)-8a-(butoxymethyl)-6-fluoro-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (24)

To a solution of 13 (8 mg, 0.015 mmol) in CH₂Cl₂ (2 mL) was added2,6-di-tert-butylpyridine (0.007 mL, 0.031 mmol) and Tf₂O (0.004 mL,0.024 mmol) at about 0° C. The mixture was stirred at about 0° C. forabout 30 minutes. To the mixture was added THF (1 mL) andtetrabutylammonium fluoride (0.3 mL of a 1M THF solution, 0.3 mmol) wasadded. The mixture was stirred at room temperature overnight. Afterconcentration in vacuo and purification by a PTLC, about 6.5 mg of 23was obtained. To a solution of 23 (4.0 mg, 0.0076 mmol) in CH₃OH (2 mL)was added Pearlman's catalyst (10 mg). The mixture was stirred under H₂(balloon pressure) for about 15 minutes. After filtration andconcentration in vacuo, about 2.9 mg of 24 was obtained.

¹H NMR (CDCl₃): δ0.92 ppm (3H, d, J=7.0), 0.93 (3H, t, J=7.1), 1.00 (3H,d, J=7.0), 1.07 (3H, d, J=7.0), 1.26 (2H, m), 1.39 (2H, m), 1.60 (2H,m), 1.87 (2H, m), 2.18 (1H, t, J=13.2), 2.21 (1H, m), 2.42 (4H, m), 3.27(1H, J=9.7), 3.52 (3H, m), 4.01 (1H, d, J=9.2), 5.18 (1H, dt, J=53.7,7.1), 6.10 (1H, d, J=2.3), 9.82 (1H, s).

EXAMPLE 13(1R,3aR,4S,8aS)-8a-(butoxymethyl)-6-cyano-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (26)

To a solution of 13 (8 mg, 0.015 mmol) in CH₂Cl₂ (2 mL) was added2,6-di-tert-butylpyridine (0.007 mL, 0.031 mmol) and Tf₂O (0.004 mL,0.024 mmol) at about 0° C. The mixture was stirred at about 0° C. forabout 30 minutes. To the mixture were added THF (1 mL) andtetrabutylammonium cyanide (82 mg, 0.31 mmol). The mixture was stirredat room temperature overnight. After concentration in vacuo andpurification by a PTLC, about 6.4 mg of 25 was obtained. To a solutionof 25 (4.0 mg, 0.0075 mmol) in CH₃OH (2 mL) was added Pearlman'scatalyst (10 mg). The mixture was stirred under H₂ (balloon pressure)for about 15 minutes. After filtration and concentration in vacuo, about2.9 mg of 26 was obtained.

¹H NMR (CDCl₃): δ0.94 ppm (3H, t, J=7.3), 1.01 (3H, d, J=6.6), 1.08 (3H,d, J=7.1), 1.10 (3H, d, J=8.0), 1.26 (2H, m), 1.39 (2H, m), 1.61 (2H,m), 1.68 (2H, m), 1.90 (2H, m), 2.14 (1H, t, J=13.2), 2.30-2.50 (4H, m),3.16 (1H, m), 3.30 (1H, d, J=9.4), 3.50 (2H, m), 4.00 (1H, d, J=9.4),6.13 (1H, d, J=2.1),9.7 (1H, s).

EXAMPLE 14(1R,3aR,4S,8aS)-8a-(butoxymethyl)-6-animo-4-formyl-3-isopropyl-7-methyl-4,4a,5,6,7,7a8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid, TFA salt (28)

To a solution of 13 (4.9 mg, 0.0094 mmol) in CH₂Cl₂ (2 mL) was added2,6-di-tert-butylpyridine (0.05 mL, 0.22 mmol) and Tf₂O (0.02 mL, 0.12mmol) at about 0° C. The mixture was stirred at about 0° C. for about 30minutes. To the mixture was added NH₃ (2 mL of a 0.5M solution indioxane, 1 mmol). The mixture was stirred at room temperature overnight.After concentration in vacuo and purification by a HPLC, about 3.0 mg of27 (as its triflate salt) was obtained. To a solution of 27 (3.0 mg,0.0057 mmol) in CH₃OH (2 mL) was added Pearlman's catalyst (10 mg). Themixture was stirred under H₂ (balloon pressure) for about 15 minutes.After filtration and concentration in vacuo, about 1.5 mg of 28 wasobtained.

¹H NMR (CDCl₃): δ0.90 ppm (3H, d, J=7.2), 0.92 (3H, t, J=7.0), 1.01 (3H,d, J=6.8), 1.03 (3H, d, J=6.9), 1.20-1.40 (4H, m), 1.50 (2H, m), 1.60(2H, m), 1.70-2.00 (4H, m), 2.25 (1H, m), 2.38 (1H, m), 2.50 (1H, m),2.76 (1H, m), 3.30 (1H, m), 3.50(1H, d, J=8.9), 3.70 (1H, d, J=8.9),3.71 (1H, m), 6.12 (1H, d, J=2.0), 9.45 (1H, s).

MS: m/z=404 (M+H).

EXAMPLE 15 Preparation of7-methyl-3-methylenehexahydro-2H-furo[2,3-c]pyran-5-yl(1E)-2,2,2-trichloroethanimidoate(37)

Step 1

To a solution of (+)-digitoxose (5 g, 0.034 mol) in CH₃CN (200 mL) wereadded EtOH (50 mL) and trifluoroacetic acid (TFA) (65 mL). The mixturewas stirred at room temperature overnight and was then concentrated invacuo. After chromatography, about 3.2 g of 29 and about 2 g of 30 wereobtained. Both isomers could be carried forward, but only 25′ 29 wasused in this example.

¹H NMR (CDCl₃): δ1.25 ppm (3H, t, J=7.1), 1.34 (3H, d, J=6.1), 1.92 (1H,dt, J=14.7, 3.4), 2.18 (1H, m), 3.16 (1H, dd, J=9.9, 3.2), 3.46 (1H, m),3.60 (1H, br), 3.78 (3H, m), 3.95 (1H, br), 4.91 (1H, d, J=3.5).Step 2

To a solution of 29 (1.79 g, 0.01 mol) in toluene (40 mL) was added 1 gof 4 Å molecular sieves and Bu₂Sn(OCH₃)₂ (3.5 mL, 0.015 mol). Themixture was refluxed overnight. At about 6° C., propargyl bromide (3.4mL of a 80% solution in toluene, 0.031 mol) and tetrabutylammoniumfluoride (TBAF) (15 mL of a 1M solution in THF, 0.015 mol) were added.The mixture was stirred at about 65° C. for about one hour. Afterfiltration, concentration in vacuo and chromatography, about 2.03 g of31 and 32 mixture was obtained, which was used directly in the nextstep.Step 3

To a solution of the 31 and 32 mixture (2.03 g) was added2,6-di-tert-butyl-pyridine (4.3 mL, 0.019 mol), followed by Tf₂O (2.1mL, 0.012 mol) at about 0° C. The mixture was stirred at roomtemperature for about one hour. After aqueous work-up (CH₂Cl₂) andchromatography, about 1.5 g of 33 was obtained. To a solution of 33(0.96 g, 2.8 mmol) in THF (10 mL) was added LiI (1.9 g, 14 mmol) at roomtemperature. The mixture was stirred at room temperature for about twohours. After aqueous work-up (CH₂Cl₂) and chromatography, about 820 mgof 34 was obtained.

¹H NMR (CDCl₃): δ1.20 ppm (3H, t, J=7.1), 1.36 (3H, d, J=6.4), 2.40 (2H,m), 2.55 (2H, m), 3.25 (1H, t, J=10.0), 3.41 (1H, m), 3.63 (1H, m), 3.78(1H, m), 4.42 (1H, m), 4.48 (1H, dd, J=15.3, 2.5), 4.57 (1H, dd, J=15.3,2.5).Step 4

To a solution of 34 (594 mg, 1.82 mmol) in toluene (10 ml) was addedBu₃SnH (0.64 mL, 2.4 mmol) followed by 2,2′-azobisisobutyronitrile(AIBN) (20 mg). The mixture was refluxed for about two hours. Afterconcentration in vacuo and chromatography, about 307 mg of 35 wasobtained. To a solution of 35 (100 mg, 0.51 mmol) in THF (5 mL) andCH₃CN (5 mL) was added HCl (5 mL of 1 N solution, 5 mmol). The mixturewas stirred at room temperature overnight. After aqueous work-up(CH₂Cl₂) and chromatography, about 76 mg of 36 was obtained in the formof both α- and β-isomers.Step 5

To a solution of 36 (56.5 mg, 0.33 mmol) in CH₂Cl₂ (5 mL) was addedCs₂CO₃ (108 mg, 0.33 mmol) followed by CCl₃CN (0.33 mL, 0.33 mmol). Themixture was stirred at room temperature for about one hour. Afterfiltration, the imidate 37(7-methyl-3-methylenehexahydro-2H-furo[2,3-c]pyran-5-yl(1E)-2,2,2-trichloroethanimidoate)obtained was concentrated and dried in vacuo and was used directly inthe coupling step without further purification.

EXAMPLE 16(1R,3aR,4S,8aS)-6-chloro-4-formyl-3-isopropyl-7-methyl-8a-{[(7-methyl-3-methylenehexahydro-2H-furo[2,3-c]pyran-5-yl)oxy]methyl}-4,4a,5,6,7,7a8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (44)

Step 1

4-methoxybenzyl(1R,3aR,4S,8aS)-4-formyl-3-isopropyl-6-[(4-methoxybenzyl)oxy]-8a-{[(4-methoxybenzyl)oxy]methyl}-7-methyl-4,4a5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylate(38)

To a solution of 1 (1 g, 1.97 mmol) in acetone (20 mL) was addedconcentrated HCl (4.5 mL). The mixture was stirred at room temperaturefor about one day. After aqueous work-up (EtOAc), 946 mg of crudeaglycone 2 was obtained and was used directly in the next step withoutpurification. To a solution of the crude aglycone 2 (946 mg) in DMF (20mL) was added para-methoxybenzyl chloride (MPMCl) (3.7 mL, 27 mmol),followed by NaH (1.1 g of a 60% oil dispersion, 27.5 mmol). The mixturewas stirred at room temperature for about one day. After aqueous work-upand chromatography, about 780 mg of 38 was obtained.

¹H NMR (CDCl₃): δ0.54 ppm (3H, d, J=7.3), 0.86 (3H, d, J=6.6), 1.05 (3H,d, J=6.9), 1.07 (1H, m), 1.18 (1H, d, J=12.8), 1.50 (1H, m), 1.64 (1H,m), 1.84 (1H, t, J=13.6), 2.01 (1H, m), 2.08 (1H, dd, J=12.5, 4.3), 2.30(1H, m), 2.42 (1H, m), 2.56 (1H, t, J=3.9), 3.43 (1H, t, J=6.1), 3.47(1H, d, J=11.0), 3.79 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.91 (1H, d,J=11.4), 4.37 (4H, s), 4.65 (1H, s), 5.06 (1H, d, J=11.6), 5.27 (1H, d,J=11.4), 6.11 (1H, d, J=2.3), 6.84-7.38 (6H, m), 9.50 (1H, s).

Step 2

4-methoxybenzyl(1R,3aR,4S,8aS)-6-chloro-4-formyl-3-isopropyl-8a-{[(4-methoxybenzyl)oxy]methyl}-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylate(40)

To a solution of 38 (723.1 mg, 1.02 mmol) in CH₂Cl₂ was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (240 mg, 1.06 mmol) andwater (1 mL). The mixture was stirred at room temperature for about twohours. After aqueous work-up (CH₂Cl₂) and chromatography, about 390 mgof 39 was obtained. To a solution of 39 (54.2 mg, 0.092 mol) in CH₂Cl₂(5 mL) at about 0° C. was added di-tert-butylpyridine (0.041 mL, 0.18mmol), followed by Tf₂O (0.023 mL, 0.14 mmol). The mixture was stirredat about 0° C. for about 30 minutes. Tetrabutylammonium chloride (512mg, 1.84 mmol) was then added. The mixture was stirred at roomtemperature overnight. After aqueous work-up (ether) and PTLC, about 47mg of 40 was obtained.

¹H NMR (CDCl₃): δ0.60 ppm (3H, d, J=7.3), 0.76 (3H, d, J=6.7), 1.00 (3H,d, J=6.8), 1.19 (1H, d, J=12.8), 1.68 (1H, t, J=13.3), 1.77 (1H, m),1.82 (2H, m), 1.97 (2H, m), 2.14 (1H, m), 2.24 (2H, m), 2.84 (1H, t,J=4.0), 3.43 (1H, d, J=9.0), 3.63 (1H, d, J=9.0), 3.82 (3H, s), 3.83(3H, s), 4.28 (2H, d, J=11.7), 4.39 (2H, d, J=11.7), 4.40 (1H, m), 5.05(2H, d, J=11.4), 5.20 (2H, d, J=11.4), 6.02 (1H, d, J=2.3), 6.84-7.36(4H, m), 9.46 (1H, s).

Step 3

(1R,3aR,4S,8aS)-8a-(hydroxyethyl)-4-formyl-3-isopropyl-6-chloro-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (41)

To a solution of 40 (40 mg, 0.066 mmol) in CH₃OH (5 mL) was addedPearlman's catalyst (10 mg). The mixture was stirred under hydrogen(balloon pressure) for about 15 minutes. After filtration andconcentration in vacuo, about 23.7 mg of 41 was obtained and useddirectly in the next step.

Step 4

[(2,2-dimethylpropanoyl)oxy]methyl(1R,3aR4S,8aS)-6-chloro-4-formyl-8a-(hydroxymethyl)-3-isopropyl-7-methyl-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylate(42)

To a solution of 41 (23.7 mg) in DMF (5 mL) was added NaHCO3 (109 mg,1.30 mmol), followed by ClCH₂OC(O)CMe₃ (0.093 mL, 0.65 mmol). Themixture was stirred at room temperature overnight. After aqueous work-up(ether) and purification by a PTLC, about 26.2 mg of 42 was obtained.

Step 5

(1R,3aR,4S,8aS)-6-chloro-4-formyl-3-isopropyl-7-methyl-8a-{[(7-methylenehexahydro-2H-furo[2,3-c]pyran-5-yl)oxy]methyl}-4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)-carboxylicacid (44)

To a solution of imidate 37 prepared above in CH₂Cl₂ (5 mL) was added 42(16 mg, 0.033 mmol) in CH₂Cl₂ (1 mL), followed by ZnCl₂ (0.6 mL of a 1Msolution in ether, 0.6 mmol). The mixture was stirred at roomtemperature for 2 hours. After aqueous work-up (CH₂Cl₂) and purificationby PTLC, about 12.6 mg of crude product 43 (•- and •-isomers) wasobtained. To a solution of this crude product 43 (4 mg) in CH₃OH (2 mL)was added K₂CO₂ (20 mg). The mixture was stirred at room temperature forabout two hours. After aqueous work-up (CH₂Cl₂) and purification byHPLC, about 1 mg of 44 was obtained.

¹H NMR (CDCl₃): δ1.00 ppm (3H, d, J=7.3), 1.01 (3H, d, J=6.8), 1.06 (3H,d, J=6.9), 1.24 (3H, d, J=6.2), 1.26 (2H, m), 1.78 (1H, dd, J=13.8,4.8), 1.82-2.08 (4H, m), 2.12 (1H, m), 2.22 (1H, m), 2.40 (3H, m), 2.56(1H, br s), 3.05 (1H, br s), 3.29 (1H, m), 3.30 (1H, d, J=9.6), 3.79(1H, t, J=7.8), 4.35 (2H, m), 4.42-4.51 (3H, m), 5.03 (1H, d, J=2.3),5.10 (1H, d, J=2.3), 6.12 (1H, d, J=2.0), 9.71 (1H, s); and MS: m/z=519(M+H).

1. A compound of formula I:

or a pharmaceutically or agriculturally acceptable salt thereof, whereinR is: (a) hydrogen, (b) C(O)OR¹, (c) C(O)NR²R³, (d) C(O)R⁴, (e)CH(R²)OR⁵, (f) C(R⁶)(R⁷)(R⁸), (g)

(h)

R¹ is: (a) (C₁-C₁₄)alkyl, (b) (C₂-C₁₄)alkenyl, (c) (C₂-C₁₄)alkynyl, (d)(C₃-C₂₀)cycloalkyl, (e) aryl or (f) aryl-(C₁-C₆)alkyl; R² and R³ areindependently: (a) H or (b) R¹; R⁴ is: (a) H, (b) R¹ or (c)(CH₂)_(m)NR²R³; R⁵ is: (a) R¹ or (b) (CH₂)_(x)O(CH₂)_(y)H; R⁶ is: (a) H,(b) (C₁-C₁₄)alkyl, (c) aryl, (d) aryl-(C₁-C₆)alkyl, (e)(CH₂)_(y)CHR⁹(CH₂)_(z)H, (f) (CH₂)_(y)C≡C(CH₂)_(z)H, (g)(CH₂)_(y)C(R⁷)═CH(CH₂)_(z)H, (h) (CH₂)_(y)C≡C(CH₂)_(m)R⁹ or (i)(CH₂)_(y)C(R⁷)═CH(CH₂)_(m)R⁹; R⁷ and R⁸ are independently: (a) H or (b)(C₁-C₁₄)alkyl; R⁹ is: (a) OH or (b) NR²R³; R¹⁰ is: (a) C(O)H or (b) CN;R¹¹ is: (a) H, (b) —CH₂CH═CH₂, (c)

(d)

X¹ and X² are independently: (a) H, wherein X¹ and X² are not Hsimultaneously, (b) (C₁-C₆)alkyl, (c) (C₁-C₆)alkoxy, (d) (C₂-C₆)alkenyloptionally substituted with R¹, (e) OH, wherein X¹ and X² are not OHsimultaneously, (f) OC[(C₁-C₆)alkyl]₃, (g) OC(O)(C₁-C₆)alkyl, (h) halo,wherein halo is F, Cl, Br or I, (i) SC(O)(C₁-C₆)alkyl, (j)S(C₁-C₆)alkyl, (k) SH, (l) N₃, (m) N[(C₁-C₆)alkyl]₂, (n)N[(C₁-C₆)alkyl]C(O)(C₁-C₆)alkyl or (o) CN; and wherein X¹ and X²together can be oxo or ═CH₂; n is: 0 or 1; m is: 1-6; p is: 0-5; x is:2-6; y is: 0-6; and z is: 0-6.
 2. The compound of claim 1, wherein R is:(a) hydrogen, (b) C(O)OR¹, (c) C(O)NR²R³, (d) C(O)R⁴, (e) CH(R²)OR⁵, (f)C(R⁶)(R⁷)(R⁸) (g)

(h)

R¹⁰ is: C(O)H; and X¹ and X² are independently: (a) H, wherein X¹ and X²are not H simultaneously, (b) (C₁-C₆)alkyl, (c) (C₁-C₆)alkoxy, (d)(C₂-C₆)alkenyl optionally substituted with R¹, (e) OH, wherein X¹ and X²are not OH simultaneously, (f) OC[(C₁-C₆)alkyl]₃, (g) OC(O)(C₁-C₆)alkyl,(h) halo, wherein halo is F, Cl, Br or I, (i) SC(O)(C₁-C₆)alkyl, (j)S(C₁-C₆)alkyl, (k) SH, (l) N₃, (m) N[(C₁-C₆)alkyl]₂, (n)N[(C₁-C₆)alkyl]C(O)(C₁-C₆)alkyl or (o)CN; and wherein X¹ and X² togethercan be oxo or ═CH₂.
 3. The compound of claim 1, wherein R is: (a)hydrogen, (b) C(O)OR¹, (c) C(O)NR²R³, (d) C(O)R⁴, (e) CH(R²)OR⁵, (f)C(R⁶)(R⁷)(R⁸), (g)

(h)

R¹⁰ is: C(O)H; R¹¹ is: H; and X¹ and X² are independently H or halo,wherein either X¹ or X² is halo.
 4. The compound of claim 1, wherein Ris: C(O)OR¹; R¹⁰ is: C(O)H; R¹¹ is: H; and X¹ and X² are independently Hor OH, wherein either X¹ or X² is OH.
 5. The compound of claim 1,wherein R is C(O)NR²R³; R¹⁰ is C(O)H; R¹¹ is H; and X¹ and X² areindependently H or OH, wherein either X¹ or X² is OH.
 6. The compound ofclaim 1, wherein R is: C(O)R⁴; R¹⁰ is: C(O)H; R¹¹ is: H; and X¹ and X²are independently H or OH, wherein either X¹ or X² is OH.
 7. Thecompound of claim 1, wherein R is: C(R²)OR⁵; R¹⁰ is: C(O)H; R¹¹ is: H;and X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.8. The compound of claim 1, wherein R is: C(R⁶)(R⁷)(R⁸); R¹⁰ is: C(O)H;R¹¹ is: H; and X¹ and X² are independently H or OH, wherein either X¹ orX² is OH.
 9. The compound of claim 1, wherein R is

R¹⁰ is C(O)H; R¹¹ is H; and X¹ and X² are independently H or OH, whereineither X¹ or X² is OH.
 10. The compound of claim 1, wherein R is

R¹⁰ is C(O)H; R¹¹ is H; and X¹ and X² are independently H or OH, whereineither X¹ or X² is OH.
 11. The compound of claim 1, wherein R is

R¹⁰ is C(O)H; R¹¹ is H; and X¹ and X² are independently H or Cl, whereineither X¹ or X² is Cl.
 12. The compound of claim 1, wherein R is:CH(R⁶)(R⁷); R¹⁰ is: C(O)H; R¹¹ is: H; R⁶ is: (a) H, (b) (C₁-C₁₄)alkyl,(c) aryl, (d) aryl-(C₁-C₆)alkyl, (e) (CH₂)_(y)CH(OH)(CH₂)_(z)H or (g)(CH₂)_(y)C(R⁷)═CH(CH₂)_(z)H; R⁷ is: H or (C₁-C₁₄)alkyl; and X¹ and X²are independently H or OH, wherein either X¹ or X² is OH.
 13. Thecompound of claim 1, wherein R¹⁰ is: C(O)H; R¹¹ is: H; R is: (a)(C₁-C₇)alkyl, (b) aryl-(C₁-C₆)alkyl, (c) (CH₂)_(y)CH═CH(CH₂)_(z)H, (d)[(C₁-C₆)alkyl]—CH₂CH═CHCH₂CH₃ or (e) [(C₁-C₆)alkyl]—CH₂CH═CH(CH₂)₂CH₃;and X¹ and X² are independently H or OH, wherein either X¹ or X² is OH.14. The compound of claim 1, wherein the compounds are:(1S,3aR,4S,8aS)-6-(acetyloxy)-8a- [(acetyloxy)methyl]-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1S,3aR,4S,8aS)-6-(methoxy)-8a- [(methoxy)methyl]-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1S,3aR,4S,8aS)-6-(propoxy)-8a- [(propoxy)methyl]-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-6- (butoxymethyl)-4-formyl-6-hydroxy-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-chloro-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-azido-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-4-formyl-6-hydroxy-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-4-formyl-3-isopropyl-6-methoxy-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-fluoro-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (butoxymethyl)-6-cyano-4-formyl-3-isopropyl-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-8a- (hydroxymethyl)-4-formyl-3-isopropyl-6-chloro-7-methyl- 4,4a,5,6,7,7a,8,8a-octahydro-1,4-methano-s-indacene-3a(1H)- carboxylic acid

(1R,3aR,4S,8aS)-6-chloro-4- formyl-3-isopropyl-7-methyl-8a-{[(7-methyl-3- methylenehexahydro-2H- furo[2,3-c]pyran-5-yl)oxy]methyl}-4,4a,5,6,7,7a,8,8a-octahydro-1,4- methano-s-indacene-3a(1H)- carboxylicacid


15. A pharmaceutical composition, which comprises a compound of formulaI according to claim 1 and a pharmaceutically acceptable carrier.
 16. Apharmaceutical formulation comprising a combination of a compound offormula I according to claim 1 and a second therapeutic agent or itspharmaceutically acceptable salt.
 17. The pharmaceutical formulation ofclaim 16, wherein the second therapeutic agent is a compound selectedfrom the group consisting of an azole, polyene, purin uncleotideinhibitor, pneumocandin derivative, echinocandin derivative, elongationfactor inhibitor, and immunomodulating agent.
 18. The pharmaceuticalformulation of claim 17, wherein the second therapeutic agent is acompound selected from the group consisting of intraconazole,flucytosine, fluconazole, and amphotericin B.
 19. An agrochemicalcomposition, which comprises a compound of formula I according to claim1 and an agriculturally acceptable carrier.
 20. An agrochemicalcomposition, which comprises a compound of formula I according to claim1 and a second active ingredient selected from the group consisting ofherbicides, insecticides, bactericides, nematocides, molluscicides,growth regulators, micronutrients, fertilizers, and fungicides.
 21. Amethod for the treatment or prevention of fungal infection in a mammal,which comprises administering to said mammal therapeutically effectiveamounts of a compound of formula I according to claim
 1. 22. A methodfor the treatment or prevention of fungal infection in a mammal, whichcomprises administering to said mammal therapeutically effective amountsof a compound of formula I according to claim 1 and a second therapeuticagent selected from the group consisting of an azole, polyene, purinnucleotide inhibitor, pneumocandin derivative, echinocandin derivative,the elongation factor inhibitor, and immunomodulating agent.
 23. Amethod for controlling phytopathogenic fungi, which comprisesadministering to a plant in need of such control therapeuticallyeffective amounts of a compound of formula I according to claim
 1. 24. Amethod for controlling phytopathogenic fungi, which comprisesadministering to a plant in need of such control therapeuticallyeffective amounts of a compound of formula I according to claim 1 and asecond active ingredient selected from the group consisting ofherbicides, insecticides, bactericides, nematocides, molluscicides,growth regulators, micronutrients, fertilizers, and fungicides.